This proposal aims to develop an 18F-labeled agonist PET probe for in vivo quantification of the G-protein coupled high affinity serotonin 1A (5-HT1A) receptors in baboon. We have two major motivations for developing an 18F labeled 5-HT1A receptor agonist radiotracer. First, we have previously shown that 5-HT1A receptors are abnormal in major depression and that elevated binding predicts response to antidepressants. One of the major impediments to using this technology in the clinic is the limited number of centers that can produce C-11 labeled radiotracers. The F-18 tracer can be shipped to multiple medical centers that are within a radius of 4 hours from the production site. Second, an agonist ligand binds preferentially to the G-protein coupled high affinity (HA) state of the receptor and thereby offers several advantages to an antagonist ligand. We have recently synthesized several 11C-labeled agonist compounds characterized by an azauracil structural skeleton that demonstrated specific binding to 5-HT1A receptors in baboon and the lead compound from the series is currently in evaluation in humans. Although this compound has many excellent properties, a limitation is that preliminary data suggest that the kinetics in two regions of interest (amygdala and hippocampus) is slow in humans. The 110-minute half-life of 18F would permit synthesis and imaging over longer duration, facilitating kinetic studies. Thus, these two issues necessitate the development of an 18F-labeled version of the agonist radiotracer by retaining the azauracil structural skeleton that survived the highly demanding toxicity and tolerance requirements. Additionally, the 18F positron energy is the lowest of the first row positron emitters and for this reason imaging can be potentially done at the highest resolution. We have designed flexible synthetic schemes for the synthesis of four 18F-labeled 5-HT1A agonists that are azauracil derivatives. MicroPET scans in adult male rats/ conventional animal dissection studies will be used for the preliminary determination of blood brain barrier permeability and biodistribution of the radiolabeled agonists. The suitable candidates will be then evaluated in baboon as potential PET imaging probes for 5-HT1A receptors. After confirming specific brain uptake in baboon by baseline and block studies, and development of metabolite analyses, the optimal modeling method will be selected on the basis of test/retest reproducibility, identifiability and time stability. Based on the results, the optimal candidate for clinical studies will be used for the in vivo quantification of HA 5-HT1A receptors in baboons. The 18F-labeled agonist PET tracer will provide a clinically useful tool to study the role of 5-HT1A receptors in the pathophysiology of neuropsychiatric disorders, for the prediction of treatment effectiveness in depression and for 5-HT1A targeted drug development. PUBLIC HEALTH RELEVANCE: The serotonin 1A receptor is implicated to play a critical role in major neuropsychiatric disorders including depression, schizophrenia, Alzheimer's disease and anxiety. This proposal aims to develop an 18F-labeled agonist PET probe for in vivo quantification of the G-protein coupled high affinity serotonin 1A receptors in baboon. The successful development of an 18F-labeled agonist PET tracer would provide a clinically useful tool to study the role of serotonin 1A receptors in the pathophysiology of neuropsychiatric disorders, for the prediction of treatment effectiveness in major depression and for the serotonin 1A receptor targeted drug development.